Transient hypofunction of NMDA receptors impairs spatial discrimination in rats.
It is hypothesized that after the arrival of cortical information conveying two similar experiences or two events close in time, the DG uses a computational process called pattern separation to orthogonalize (or maximize) the differences in the incoming information onto area CA3 (Yassa and Stark, 2011; Santoro, 2013). This neural mechanism is believed to facilitate the proper storage of similar neuronal information as independent events and prevent the overlapping of new memories. We hypothesized that, if the DG’s integrity is compromised due to transient hypofunction of NMDARs, the behavioral activity in which the DG participates will also be compromised. To explore this possibility, we evaluated MK-801-treated animals’ ability to discriminate small changes in the spatial configuration of identical objects maintained in a familiar environment (Santoro, 2013). The discrimination index (DI) of this behavioral test was evaluated by alternating the spatial configuration of identical objects in a familiar environment (see Figure 9a for a schematic representation). A series of spatial positions (P) was used to determine the minimal displacement position of one object vs. another at which the animal perceived the change in spatial position. This cognitive ability increases the demand for spatial pattern separation activity (van Goethem et al., 2018).
In control animals, we corroborated that the DI depends on the magnitude of displacement of one object (Figure 9b), a phenomenon previously reported in adult animals (van Goethem et al., 2018). On the other hand, MK-801-treated animals efficiently differentiated the change in the spatial position of objects when displacement was maximal (DI in P5 from control vs. MK-801: 0.41 ± 0.035 vs. 0.43 ± 0.07; n = 10 for the control group and n = 12 for MK-801 group), and exhibited comparable DI values in the absence of object displacement (DI in P1 from control vs. MK-801: 0.001 ± 0.021 vs. -0.01 ± 0.011). However, when the magnitude of one object’s displacement was gradually reduced from P4 to P2, the MK-801-treated animals’ discrimination ability was reduced (DI in P4 from control vs. MK-801: 0.38 ± 0.04 vs. 0.17 ± 0.05; DI in P3 from control vs. MK-801: 0.25 ± 0.03 vs. 0.1 ± 0.04; DI in P2 from control vs. MK-801: 0.07 ± 0.03 vs. 0.001 ± 0.01). These differences in DI values were significant at P3 (two-way RM ANOVA, treatment effect: F(1, 20) = 8.225, P < 0.01; Holm–Šidák post-hoc test, P < 0.05). The heatmaps in Figure 9c show the spatial discrimination performance for both experimental conditions. Although MK-801-treated animals efficiently discriminate new object positions when the magnitude of the displacement is maximal (P5), their mnemonic ability for spatial discrimination is reduced when the magnitude of displacement of one object is gradually narrowed, a condition that increases the demand of spatial pattern separation (Figure 9d). Together, these results suggest that impaired spatial discrimination in response to transient blockade of NMDARs may reflect impaired pattern separation associated with psychiatric disorders such as schizophrenia (Faghihi and Moustafa, 2015).